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WNK1 kinase and its partners Akt, SGK1 and NBC-family Na⁺/HCO3^- cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling.

ABSTRACT: Glioblastoma is a highly heterogeneous brain tumor. The presence of cancer cells with stem-like and tumor initiation/propagation properties contributes to poor prognosis. Glioblastoma cancer stem-like cells (GSC) reside in hypoxic and acidic niches favoring cell quiescence and drug resistance. A high throughput screening recently identified the laxative Bisacodyl as a cytotoxic compound targeting quiescent GSC placed in acidic microenvironments. Bisacodyl activity requires its hydrolysis into DDPM, its pharmacologically active derivative. Bisacodyl was further shown to induce tumor shrinking and increase survival in in vivo glioblastoma models. Here we explored the cellular mechanism underlying Bisacodyl cytotoxic effects using quiescent GSC in an acidic microenvironment and GSC-derived 3D macro-spheres. These spheres mimic many aspects of glioblastoma tumors in vivo, including hypoxic/acidic areas containing quiescent cells. Phosphokinase protein arrays combined with pharmacological and genetic modulation of signaling pathways point to the WNK1 serine/threonine protein kinase as a mediator of Bisacodyl cytotoxic effect in both cell models. WNK1 partners including the Akt and SGK1 protein kinases and NBC-family Na⁺/HCO3^- cotransporters were shown to participate in the compound's effect on GSC. Overall, our findings uncover novel potential therapeutic targets for combatting glioblastoma which is presently an incurable disease.

SUBMITTER: Chen W

PROVIDER: S-EPMC6007472 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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WNK1 kinase and its partners Akt, SGK1 and NBC-family Na<sup>+</sup>/HCO3<sup>-</sup> cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling.

Chen Wanyin W Zebaze Leonel Nguekeu LN Dong Jihu J Chézeau Laëtitia L Inquimbert Perrine P Hugel Sylvain S Niu Songlin S Bihel Fréderic F Boutant Emmanuel E Réal Eléonore E Villa Pascal P Junier Marie-Pierre MP Chneiweiss Hervé H Hibert Marcel M Haiech Jacques J Kilhoffer Marie-Claude MC Zeniou Maria M

Oncotarget 20180605 43

Glioblastoma is a highly heterogeneous brain tumor. The presence of cancer cells with stem-like and tumor initiation/propagation properties contributes to poor prognosis. Glioblastoma cancer stem-like cells (GSC) reside in hypoxic and acidic niches favoring cell quiescence and drug resistance. A high throughput screening recently identified the laxative Bisacodyl as a cytotoxic compound targeting quiescent GSC placed in acidic microenvironments. Bisacodyl activity requires its hydrolysis into DD ...[more]

PMID: 29930759

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Dataset Information

WNK1 kinase and its partners Akt, SGK1 and NBC-family Na⁺/HCO3^- cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling.

Publications

WNK1 kinase and its partners Akt, SGK1 and NBC-family Na<sup>+</sup>/HCO3<sup>-</sup> cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling.

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Dataset Information

WNK1 kinase and its partners Akt, SGK1 and NBC-family Na+/HCO3- cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling.

Publications

WNK1 kinase and its partners Akt, SGK1 and NBC-family Na<sup>+</sup>/HCO3<sup>-</sup> cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

WNK1 kinase and its partners Akt, SGK1 and NBC-family Na⁺/HCO3^- cotransporters are potential therapeutic targets for glioblastoma stem-like cells linked to Bisacodyl signaling.